There is immense potential to generate a variety of bioactive lipids in the lung in response to injury and infection. The central theme of this proposal is that lipid mediators have diverse functions in controlling the amplitude of the inflammatory response and its resolution. Our goals are to define the role of specific lipid mediators in protecting the lung during inflammatory injury and infection, and to determine how the environmental toxicant ozone induces production of novel lipid metabolites that interfere with these processes leading to pathological consequences. The objectives are to: Elucidate mechanisms of Group IVA cytosolic phospholipase A2 activation and eicosanoid production in resident peritoneal and alveolar macrophages by Cantjida albicans and Aspergillus fumigatus, and determine the role of this pathway in regulating immune responses to fungal infection in the lung. Define the mechanisms of production of the novel lipid mediator lysophosphatidylserine by neutrophils and macrophages, and determine how it mediates the removal of apoptotic cells and suppresses pro-inflammatory cytokine production to promote the resoiution of lung inflammation. Structurally characterize by mass spectrometry novel lipid mediators produced following exposure of lung surfactant to low levels of ozone, and to determine their impact on the ability of the lung to control inflammation and infection. Novel mass spectrometry approaches will be developed to image these lipid mediators in ozonized lung tissues. This program brings together investigators with diverse expertise in cell biology, biochemistry and structural biology. By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses.

P01HL034303

1985-09-30

2018-01-31